Dysmenorrhea is a common repetitive disorder affecting female adolescents and women, and is closely associated with the menstrual cycle. Over the years, there has been a widespread mischaracterization of dysmenorrhea as simply a painful menstruation or menstrual cramping. There are several types of dysmenorrhea, as defined for example in Taber's Cyclopedic Medical Dictionary (12.sup.th edition). However, the two types that are most prevalent and most prevalently studied are primary dysmenorrhea and secondary dysmenorrhea. In primary dysmenorrhea there is no underlying or associated organic pathology of either the uterus, fallopian tubes, or ovaries. Where an organic pathology of the type just mentioned does exist, the resulting dysmenorrhea is termed secondary. Some causes of secondary dysmenorrhea are endometriosis, uterine myomas (and polyps and adhesions), ovarian cysts, adenomyosis, pelvic inflammatory disease (PID), and the presence of an intrauterine device. For a thorough modern day treatment of the etiologic bases of dysmennorrhea and premenstrual syndrome, including studies and a historical perspective of therapy regimens, see, for example, Dawood M.D., M. Y. et al, "Premenstrual Syndrome and Dysmenorrhea", (Urban & Schwarzenberg 1985) incorporated herein in pertinent part by reference.
While primary and secondary dysmenorrheas require different management or therapy (the latter type usually requiring surgery), both types involve increased levels of prostaglandin synthesis. The increased prostaglandin synthesis results from the loss of hormonal support at menses (i.e., low progesterone), which triggers the release of arachidonic acid from phospholipids under the action of phospholipase A.sub.2. Arachidonic acid is the essential starting material for prostaglandin biosynthesis, in the presence of the enzyme cyclooxygenase. Prostaglandins are smooth muscle-stimulating agents, hence giving rise to increased uterine contractility. The major prostaglandins involved in uterine function are PGE.sub.2, PGF.sub.2.sub..sub..alpha. , and PGI.sub.2 (prostacyclin). The key role of prostaglandins in dysmenorrhea was first noted in 1957 by Pickles, who observed their presence in menstrual fluid. Pickles later identified the principle component of the prostaglandins as a mixture of PGF.sub.2.sub..sub..alpha. and PGE.sub.2. Another researcher by the name of von Euler pin-pointed PGF.sub.2.sub..sub..alpha. (also known as "prostaglandin F.sub.2.sub..sub..alpha. ") as the agent responsible for stimulating the normal expulsive contractions of the myometrium. Hence, the symptomology of dysmenorrhea resembles that of the side effects of prostaglandin admininstration. Namely, nausea, vomiting, diarrhea, vasoconstriction (i.e., uterine ischemia), and severe uterine cramps. Irritability and other psychological disturbances are also symptoms of dysmenorrhea. The physical pain of dysmenorrheic uterine cramping or hypercontractility is directly the result of increased production of prostaglandin F.sub.2.sub..sub..alpha. either before or with onset of menstruation.
The modalities for managing or treating primary dysmenorrhea are different from those for managing or treating secondary dysmenorrhea. This is due in large part to the fact that the latter almost always ultimately requires a surgical intervention (oftentimes preceded by an unsuccessful attempt at drug therapy), whereas the former can be effectively brought under control by administering drug therapy.
The chief therapies for primary dysmenorrhea are administration of oral contraceptives (endocrine therapy) and prostaglandin synthetase inhibitors. Essentially all non-steroidal antiinflammatory agents (NSAIDS) fall into the latter group. Oral contraceptives are the ideal choice for treating a dysmenorrheic woman where that woman's primary objective is birth control. Birth control pills are believed to reduce prostaglandin levels in menstrual fluid by 1) reducing the volume of menstrual fluid by suppression of endometrial tissue growth, and 2) by inhibiting ovulation, thereby creating an endocrine milieu wherein prostaglandins are low and luteal phase progesterone levels, believed to be necessary for prostaglandin biosynthesis, are absent. However, oral contraceptives are not the primary choice of birth control for all women of child-bearing years for a number of reasons. For example, birth control pills carry numerous contraindications, and they must be taken regularly at least three (sometimes four) weeks of the month.
Prostaglandin synthetase inhibitors (PSIs), on the other hand, are given typically 2-3 days of the menstrual cycle for treating primary dysmenorrhea. There are two types of PSIs. Type I prostaglandin synthetase inhibitors are those that inhibit the enzyme cyclo-oxygenase, thereby blocking the conversion of arachidonic acid to cyclic endoperoxides. Type II prostaglandin synthetase inhibitors are those that inhibit the isomerase and reductase enzymes, thereby preventing the conversion of endoperoxide to prostaglandin. NSAIDS that are type I PSIs include aspirin, indomethacin, meclofenamic acid, and ibuprofen. NSAIDS that are type II PSIs include phenylbutazone and p-chloromercuribenzoate. A large number of compounds fall under the umbrella of NSAIDS and all demonstrate, in varying degrees, the ability to inhibit prostaglandin synethesis. These include aryl carboxylic and arylalkanoic acids, acetic acid analogs, propionic acid analogs, fenamates, and enolic acids (including pyrazolidinediones). While NSAIDS are predominantly the treatment of choice for primary dysmenorrhea over oral contraceptives, NSAIDS are not without side effects. The predominant side effects are various gastrointestinal disorders (e.g., gastric ulceration), renal dysfunction, and disturbances of the central nervous system (e.g., headache, dizziness, and drowsiness).
Other drug-related therapies for dysmenorrhea include progesterone-medicated intrauterine devices, and calcium antagonists (to inhibit muscle contraction). Limited efficacy has been observed with administration of betamimetic agents, and tocolytic agents (i.e., ethanol).
The management of secondary dysmenorrhea generally entails elucidating the underlying organic pathology and correcting it usually with surgery. Any medicinal therapy administered to a woman with secondary dysmenorrhea is an interim measure to bring some relief of symptoms while the underlying pathology is elucidated and/or the patient awaits appropriate surgery. However, there are certain instances of secondary dysmenorrhea where a medicinal management is appropriate. For example, women who develop dysmenorrhea from the use of an IUD should be prescribed an effective prostaglandin synthetase inhibitor. Also, hormone therapies, e.g., with danazol and certain gonadotropin releasing hormone analogues, have been effective in relieving the dysmenorrhea and pelvic pain caused by endometriosis. Combination therapy of danazol in conjunction with oral contraceptives has been shown not only to relieve the pain associated with endometriosis, but also to cause a regression of the disorder.
Admittedly, great strides have been made in the past forty years in the understanding of the nature and types of dysmenorrhea, as well as in how to manage or treat this disorder that affects most, if not all, of adolescent females and women. While the benefits offered by the highly efficacious prostaglandin synthetase inhibitors (NSAIDS) seem to outweigh their side effects, and the same could possibly be said for oral contraceptive therapy, there is still a need in the art for the discovery of other regimens of equal or greater efficacy to NSAIDS, while having far fewer contraindications for the management of dysmenorrhea, endometriosis, and pre-term labor.
Carnouvis, C. P. et al, Am. J. Physiol., 255, F685-9 (1988) and Burch, R. M. et al, J. Pharmacol. Exp. Ther., 210, 344-8 (1979) have demonstrated in in vitro studies with toad urinary bladder preparations that histidine decreased PGE.sub.2 synthesis therein. Steinhauer, H. B. et al, Clin. Nephrol., 24, 63-68 (1985) report that histidine diminishes PGE.sub.2 and thromboxane B.sub.2 levels in spontaneous murine autoimmune disease. Also, Steinhauer, H. B. et al, Prostaglandins Leukotrienes Med., 13, 211-16 (1984).
However, as yet unrecognized or suggested in the art, the present invention is based on the discovery that the amino acid histidine is both effective and highly safe in alleviating a number of reproductive disorders, and/or at least certain symptoms thereof, in the human female and in other women.